**3. Cardiovascular effects on adipocytokines**

Over the last two decades adipose tissue had established as a dynamic organ that carries out several important physiological processes. It is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis [27]. It also secretes numerous peptide hormones such as leptin, adiponectin, resistin and many others [28, 29]. Generally, there are three types of adipose tissue in humans which are white adipose tissue (WAT), brown adipose tissue (BAT) and beige/brite/brown-like adipose tissue (bAT). Different types of adipose tissue have distinct morphologies in reflecting their distinct functions [30] (**Figure 2**).

WAT is a major component of body's adipose tissue that provides most of the total body fat and source of fatty acids which are used as energy substrates for the generation of energy through oxidative phosphorylation of adenosine triphosphate (ATP) high-energy bond [31, 32]. Excess accumulation of WAT is potential in developing obesity and obesity-related diseases. There are three types of obesity which are android obesity, central obesity and gynoid obesity. Android or Central obesity is related to the accumulation of WAT at the upper part of body which is potentially related to some inflammatory pathologies. Meanwhile, gynoid obesity is related to the accumulation of WAT at lower part of body which does not affect any metabolic complication (**Figure 2**) [31, 32].

**97**

the body [34, 35].

**Figure 2.**

*Types of adipose tissue.*

**3.1 Role of adiponectin**

*The Mechanistic and Pathophysiological Role of Adiponectin and Resistin towards Regulation…*

Anatomically, WAT contains two main depots around internal organs which are subcutaneous WAT (SAT) and visceral WAT (VAT). WAT contributes to the whole body insulation and endocrine functions including secretion of leptin, TNF-, adiponectin, resistin, and other compounds related to the degree of obesity and insulin sensitivity. It is located in the peritoneal cavity, where it forms a compact tissue, or as single adipocytes. Adipocytes contain a single lipid droplet which is known as univacuolar adipocytes. It can be measured between 40 and 120 μm because the size of the lipid droplet may differ significantly [33]. WAT exhibits many essential physiological roles, including the triglyceride accumulation of postprandial glucose and the secretion of signaling factors to control appetite and energy homeostasis. In periods of energy demand by the body, WAT plays role to store excess lipids in the form of triglycerides (TG) and releasing free fatty acids (FFA). It often synthesizes

The general term for a bioactive substance formed by adipose tissue is known as adipocytokine or adipokine. It is a type of peptide that link the function of adipose tissue to the brain and other target organs [34]. Adipocytokine are hormones formed by fat tissues and play a role in energy homeostasis, the metabolism of sugar and fat, regulation of thermogenesis, reproduction and immunity. They also affect cardiovascular function, either through direct action by paracrine effects on the vascular wall or by influencing endothelial function through altered adipokine plasma and tissue levels relative to the total mass of adipose tissue in

Adiponectin is an abundant circulating hormone present in at least three multimeric forms: trimers, hexamers, and high-molecular-weight (HMW) complexes. Among them, the HMW oligomer is major active form mediating the insulin-sensitizing and cardiovascular protective effects of the adipokine [36–38]. Adiponectin is a protein hormone with 244 amino acids derived from adipose tissue and mainly target adiponectin receptors in regulating energy metabolism and exerts functions such as antiatherogenic, anti-inflammatory, anti-diabetic and cardioprotective effect [39]. It is primarily found in WAT and also could be found in osteoblast, skeletal muscle and cardiomyocytes [40]. Adiponectin's activity is contrary to the function of leptin and resistin. It has two widely expressed receptors (AdipoR1 and AdipoR2) which cross the cerebrospinal fluid in the brain [41].

and releases adipokines that control metabolic homeostasis.

*DOI: http://dx.doi.org/10.5772/intechopen.96171*

*The Mechanistic and Pathophysiological Role of Adiponectin and Resistin towards Regulation… DOI: http://dx.doi.org/10.5772/intechopen.96171*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

Energy balance requires an ability of the brain to detect the status of energy stores and match energy intake with expenditure. Dysregulation of appetite and impaired energy expenditure causes excessive food consumption and disrupt the energy balance. In addition, it will cause repeated sense of hunger which contributes to the development of visceral obesity and metabolic syndrome. Frequent intakes of food expose body to store extra calorie which will turn into fat and distribute in different parts of body. There are few hunger hormones known for generating hunger state such as resistin, leptin and ghrelin involve in this process [26]. Previous study mentioned that uncontrolled eating habits like diminishing the frequency of eating, repeated fasting and recurrent over eating were link with obesity-related disorder

*The circulation of dual-Centre theory related to blood glucose on hunger and satiety.*

such as cardiovascular disease, insulin resistance and inflammation [26].

Over the last two decades adipose tissue had established as a dynamic organ that carries out several important physiological processes. It is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis [27]. It also secretes numerous peptide hormones such as leptin, adiponectin, resistin and many others [28, 29]. Generally, there are three types of adipose tissue in humans which are white adipose tissue (WAT), brown adipose tissue (BAT) and beige/brite/brown-like adipose tissue (bAT). Different types of adipose tissue have distinct morphologies in reflecting their distinct func-

WAT is a major component of body's adipose tissue that provides most of the total body fat and source of fatty acids which are used as energy substrates for the generation of energy through oxidative phosphorylation of adenosine triphosphate (ATP) high-energy bond [31, 32]. Excess accumulation of WAT is potential in developing obesity and obesity-related diseases. There are three types of obesity which are android obesity, central obesity and gynoid obesity. Android or Central obesity is related to the accumulation of WAT at the upper part of body which is potentially related to some inflammatory pathologies. Meanwhile, gynoid obesity is related to the accumulation of WAT at lower part of body which does not affect any metabolic

**3. Cardiovascular effects on adipocytokines**

**96**

tions [30] (**Figure 2**).

**Figure 1.**

complication (**Figure 2**) [31, 32].

Anatomically, WAT contains two main depots around internal organs which are subcutaneous WAT (SAT) and visceral WAT (VAT). WAT contributes to the whole body insulation and endocrine functions including secretion of leptin, TNF-, adiponectin, resistin, and other compounds related to the degree of obesity and insulin sensitivity. It is located in the peritoneal cavity, where it forms a compact tissue, or as single adipocytes. Adipocytes contain a single lipid droplet which is known as univacuolar adipocytes. It can be measured between 40 and 120 μm because the size of the lipid droplet may differ significantly [33]. WAT exhibits many essential physiological roles, including the triglyceride accumulation of postprandial glucose and the secretion of signaling factors to control appetite and energy homeostasis. In periods of energy demand by the body, WAT plays role to store excess lipids in the form of triglycerides (TG) and releasing free fatty acids (FFA). It often synthesizes and releases adipokines that control metabolic homeostasis.

The general term for a bioactive substance formed by adipose tissue is known as adipocytokine or adipokine. It is a type of peptide that link the function of adipose tissue to the brain and other target organs [34]. Adipocytokine are hormones formed by fat tissues and play a role in energy homeostasis, the metabolism of sugar and fat, regulation of thermogenesis, reproduction and immunity. They also affect cardiovascular function, either through direct action by paracrine effects on the vascular wall or by influencing endothelial function through altered adipokine plasma and tissue levels relative to the total mass of adipose tissue in the body [34, 35].

#### **3.1 Role of adiponectin**

Adiponectin is an abundant circulating hormone present in at least three multimeric forms: trimers, hexamers, and high-molecular-weight (HMW) complexes. Among them, the HMW oligomer is major active form mediating the insulin-sensitizing and cardiovascular protective effects of the adipokine [36–38]. Adiponectin is a protein hormone with 244 amino acids derived from adipose tissue and mainly target adiponectin receptors in regulating energy metabolism and exerts functions such as antiatherogenic, anti-inflammatory, anti-diabetic and cardioprotective effect [39]. It is primarily found in WAT and also could be found in osteoblast, skeletal muscle and cardiomyocytes [40]. Adiponectin's activity is contrary to the function of leptin and resistin. It has two widely expressed receptors (AdipoR1 and AdipoR2) which cross the cerebrospinal fluid in the brain [41].

Plasma protein contains 0.01% of adiponectin and in normal human subjects it is found about 3 to 30 ug/ml [42, 43].

In order to regulate the metabolism of fatty acids, carbohydrates, cholesterol and amino acids, as well as mitochondrial function, autophagy and the growth of cells, both receptors are critical in inducing AMP-activated protein kinase (AMPK) activity. In addition, both receptors are also important in energy balance and energy expenditure as these processes activate CNS and peripheral metabolic system to trigger metabolic processes. The brain suppresses feeding activity in the event of elevated energy consumption or induces the accumulation of surplus energy in other tissues, such as glycogen in liver or triglycerides in adipose tissue [44].

On the other hand, when energy expenditure is greater than energy intake, it increases appetite and reduces energy expenditure through different metabolic pathways, including metabolism of fatty acids and activation of the AMP-activated protein kinase nutrient sensor (AMPK) [44]. Besides that, AdipoR2 contrarily enhances glucose consumption by regulating their gene expression via PPAR-α signaling pathway. Therefore, adiponectin improves hepatic insulin resistance by making balance via reducing glycogenesis and lipogenesis and increase glucose consumption [45]. Besides that, adiponectin receptors also ameliorate vascular dysfunction via activation of endothelial nitric oxide (NO) production and antiatherogenic effects by inhibiting the inflmmtion in the various vasculature [46–50].

The administration of adiponectin via intracerebroventricular showed increase in energy consumption and decrease in food intake. It has also been suggested as a mediator of the fasting metabolic response. Previous research has shown that food intake rises, energy expenditure decreases and weight increases occur when adiponectin is administered peripherally to mimic rising levels during fasting. These results were associated with increases in hypothalamus of AMP kinase activity expression [41, 51]. Other than that, an elevation of adiponectin in plasma by either pharmacological or genetic approaches alleviates obesity-induced endothelial dysfunction and also prevents atherosclerosis, myocardial infarction and diabetic cardiomyopathy [36].

At the chromosome 3q27, there is a gene that codes the human adiponectin has been reported by Genom-wide association studies (GWAS), and is linked with susceptibility to diabetes and CVD [36, 52]. Meanwhile, Al Khadli [53] reported that human adiponectin gene exists on chromosome 3q26 which associated with type 2 diabetes mellitus and metabolic syndrome susceptibility [40]. The hypertrophic cardiomyopathy studies show that overexpression of adiponectin had reduced the hyperthrophy by activating the AMPK and inhibits the hypertrophic response to α-adrenergic receptor stimulation [21, 54]. The AMPK activation has been shown to inhibit protein synthesis in cardiac myocytes, which is mediated by decrease in phosphorylation of p70S6 kinase and increase in eukaryotic elongation factor-2 phosphorylation [21, 55]. Adiponectin's anti-hypertrophic activities on AMPK are thought to occur via the receptors of AdipoR1 and R2 [21, 56].

Besides a study reported that adiponectin gene mutation causes cellular secretion impairment by preventing trimer assemblage and is clinically associated with hypoadiponectinemia. Hypoadiponectinemia is a condition referred as low concentration of adiponectin as compare to the baseline [40, 57, 58]. In vivo study found that high fat diet causes adiponectin resistance by inhibiting the receptor expression which impacts on the reduction of adiponectin concentration. Adiponectin resistance in skeletal muscle and liver tissue causes development of systemic hyperglycemia and hyperlipidemia consequently causes vascular injury and cardiovascular complications. Cytokine production such as Tumor Necrosis Factor-alpha (TNFα) plays a critical pathogenic role in cardiovascular complication and it is significantly higher in obese or diabetic individuals [59]. There are many in-vivo studies which

**99**

*The Mechanistic and Pathophysiological Role of Adiponectin and Resistin towards Regulation…*

However, diet high in polyunsaturated fatty acids (PUFAs) especially omega-3 potentially increases the gene expression and plasma level of adiponectin [60]. PUFAs are simply fat molecules that have more than one unsaturated carbon bond in the molecule. Omega and omega-6 are the type of PUFAs which cannot be made by the body and should be obtained via dietary sources. Fish oil consumption presented an association to increase the concentration of adiponectin. Generally, omega-3 PUFAs are perceived as a beneficial dietary intervention to enhance the

In 2001, resistin was firstly discovered in mice with abundantly found in WAT and has ability to act on insulin resistance actions which link between obesity and diabetes. In mice, studies found that resistin is expressed in several cell types such as intestinal epithelium, skeletal muscle cells, astrocytes and adipocytes. Human resistin is a 12.5 kDa cysteine-rich peptide with a mature sequence consisting of 108 amino acids and located at chromosome 19. It is primarily produced by peripheral blood mononuclear cells (PBMCs), macrophages, bone marrow and

Resistin exists in three forms which are trimer, hexamer and a monomer, with lower molecular weight form being the most active [64, 65]. Decorin is a functional receptor for resistin and was identified on the surface of adipose tissue progenitor cells [64, 66]. The normal serum concentration of resistin in human is between 7 to 22 ng/mL−1 [62, 63]. While in obese and diabetic patient, resistin was reported higher than normal reading. A few studies mentioned that, there is a correlation shown between resistin expression with inflammatory markers, coronary artery disease and CVDs in patients with Mets [62, 67, 68]. Jonas [69] mentioned that participant who is suffered from hypertension and diagnosed with metabolic

Resistin is emerging as an important biomarker and therapeutic target for coronary artery disease and others. It also appears to be involved in angiogenesis, thrombosis and vascular smooth muscle cell (VSMC) migration and proliferation which contribute to atherosclerosis [62]. Toll Like receptor 4 (TLR-4) is the earliest confirmed resistin receptor which is known as a major mediator in innate and adaptive immune responses stimulated by lipopolysaccharide (LPS) [70, 71] while Adenylyl Cyclase-Associated Protein 1 (CAP1) is also a resistin receptor which selected out by immunoglobulin assay [70, 72]. TLR-4 and CAP1 play a role in atherogenesis from endothelial dysfunction to diverse terminal outcome with

A study done by Gencer [73] found that there was an association between resistin and increased risk of CVD events independently of clinical variable. Resistin promotes expression of pro-atherogenic molecules such as Intracellular Adhesion molecule −1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1), Monocyte chemo-attractant protein-1 (MCP-1) and Endothelial-1 (ET-1), down regulates anti-atherogenic molecules and implicated in the first stage of the atherosclerosis

On the other hand, high fat diet will cause body fat mass increment which can influence the level of resistin and cause insulin resistance and inflammation. Low High Density Lipoprotein (HDL), high triglyceride and high Low Density Lipoprotein (LDL) are characterize as atherogenic dyslipidemia while resistin will induce dyslipidemia to accelerate atherogenesis [70]. A study done by Leon et al. [74]

supported that decrease level of adiponectin significantly the obesity status,

adiponectin levels for the prevention and treatment of CVDs [61].

*DOI: http://dx.doi.org/10.5772/intechopen.96171*

hypertension and type-2 diabetes.

**3.2 Role of resistin**

adipocytes [62, 63].

various pathways.

syndrome shows high level of resistin.

process via endothelial cell activation.

*The Mechanistic and Pathophysiological Role of Adiponectin and Resistin towards Regulation… DOI: http://dx.doi.org/10.5772/intechopen.96171*

supported that decrease level of adiponectin significantly the obesity status, hypertension and type-2 diabetes.

However, diet high in polyunsaturated fatty acids (PUFAs) especially omega-3 potentially increases the gene expression and plasma level of adiponectin [60]. PUFAs are simply fat molecules that have more than one unsaturated carbon bond in the molecule. Omega and omega-6 are the type of PUFAs which cannot be made by the body and should be obtained via dietary sources. Fish oil consumption presented an association to increase the concentration of adiponectin. Generally, omega-3 PUFAs are perceived as a beneficial dietary intervention to enhance the adiponectin levels for the prevention and treatment of CVDs [61].

#### **3.2 Role of resistin**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

found about 3 to 30 ug/ml [42, 43].

cardiomyopathy [36].

Plasma protein contains 0.01% of adiponectin and in normal human subjects it is

In order to regulate the metabolism of fatty acids, carbohydrates, cholesterol and amino acids, as well as mitochondrial function, autophagy and the growth of cells, both receptors are critical in inducing AMP-activated protein kinase (AMPK) activity. In addition, both receptors are also important in energy balance and energy expenditure as these processes activate CNS and peripheral metabolic system to trigger metabolic processes. The brain suppresses feeding activity in the event of elevated energy consumption or induces the accumulation of surplus energy in other tissues, such as glycogen in liver or triglycerides in adipose tissue [44].

On the other hand, when energy expenditure is greater than energy intake, it increases appetite and reduces energy expenditure through different metabolic pathways, including metabolism of fatty acids and activation of the AMP-activated protein kinase nutrient sensor (AMPK) [44]. Besides that, AdipoR2 contrarily enhances glucose consumption by regulating their gene expression via PPAR-α signaling pathway. Therefore, adiponectin improves hepatic insulin resistance by making balance via reducing glycogenesis and lipogenesis and increase glucose consumption [45]. Besides that, adiponectin receptors also ameliorate vascular dysfunction via activation of endothelial nitric oxide (NO) production and antiatherogenic effects by inhibiting the inflmmtion in the various vasculature [46–50]. The administration of adiponectin via intracerebroventricular showed increase in energy consumption and decrease in food intake. It has also been suggested as a mediator of the fasting metabolic response. Previous research has shown that food intake rises, energy expenditure decreases and weight increases occur when adiponectin is administered peripherally to mimic rising levels during fasting. These results were associated with increases in hypothalamus of AMP kinase activity expression [41, 51]. Other than that, an elevation of adiponectin in plasma by either pharmacological or genetic approaches alleviates obesity-induced endothelial dysfunction and also prevents atherosclerosis, myocardial infarction and diabetic

At the chromosome 3q27, there is a gene that codes the human adiponectin has been reported by Genom-wide association studies (GWAS), and is linked with susceptibility to diabetes and CVD [36, 52]. Meanwhile, Al Khadli [53] reported that human adiponectin gene exists on chromosome 3q26 which associated with type 2 diabetes mellitus and metabolic syndrome susceptibility [40]. The hypertrophic cardiomyopathy studies show that overexpression of adiponectin had reduced the hyperthrophy by activating the AMPK and inhibits the hypertrophic response to α-adrenergic receptor stimulation [21, 54]. The AMPK activation has been shown to inhibit protein synthesis in cardiac myocytes, which is mediated by decrease in phosphorylation of p70S6 kinase and increase in eukaryotic elongation factor-2 phosphorylation [21, 55]. Adiponectin's anti-hypertrophic activities on AMPK are

Besides a study reported that adiponectin gene mutation causes cellular secretion impairment by preventing trimer assemblage and is clinically associated with hypoadiponectinemia. Hypoadiponectinemia is a condition referred as low concentration of adiponectin as compare to the baseline [40, 57, 58]. In vivo study found that high fat diet causes adiponectin resistance by inhibiting the receptor expression which impacts on the reduction of adiponectin concentration. Adiponectin resistance in skeletal muscle and liver tissue causes development of systemic hyperglycemia and hyperlipidemia consequently causes vascular injury and cardiovascular complications. Cytokine production such as Tumor Necrosis Factor-alpha (TNFα) plays a critical pathogenic role in cardiovascular complication and it is significantly higher in obese or diabetic individuals [59]. There are many in-vivo studies which

thought to occur via the receptors of AdipoR1 and R2 [21, 56].

**98**

In 2001, resistin was firstly discovered in mice with abundantly found in WAT and has ability to act on insulin resistance actions which link between obesity and diabetes. In mice, studies found that resistin is expressed in several cell types such as intestinal epithelium, skeletal muscle cells, astrocytes and adipocytes. Human resistin is a 12.5 kDa cysteine-rich peptide with a mature sequence consisting of 108 amino acids and located at chromosome 19. It is primarily produced by peripheral blood mononuclear cells (PBMCs), macrophages, bone marrow and adipocytes [62, 63].

Resistin exists in three forms which are trimer, hexamer and a monomer, with lower molecular weight form being the most active [64, 65]. Decorin is a functional receptor for resistin and was identified on the surface of adipose tissue progenitor cells [64, 66]. The normal serum concentration of resistin in human is between 7 to 22 ng/mL−1 [62, 63]. While in obese and diabetic patient, resistin was reported higher than normal reading. A few studies mentioned that, there is a correlation shown between resistin expression with inflammatory markers, coronary artery disease and CVDs in patients with Mets [62, 67, 68]. Jonas [69] mentioned that participant who is suffered from hypertension and diagnosed with metabolic syndrome shows high level of resistin.

Resistin is emerging as an important biomarker and therapeutic target for coronary artery disease and others. It also appears to be involved in angiogenesis, thrombosis and vascular smooth muscle cell (VSMC) migration and proliferation which contribute to atherosclerosis [62]. Toll Like receptor 4 (TLR-4) is the earliest confirmed resistin receptor which is known as a major mediator in innate and adaptive immune responses stimulated by lipopolysaccharide (LPS) [70, 71] while Adenylyl Cyclase-Associated Protein 1 (CAP1) is also a resistin receptor which selected out by immunoglobulin assay [70, 72]. TLR-4 and CAP1 play a role in atherogenesis from endothelial dysfunction to diverse terminal outcome with various pathways.

A study done by Gencer [73] found that there was an association between resistin and increased risk of CVD events independently of clinical variable. Resistin promotes expression of pro-atherogenic molecules such as Intracellular Adhesion molecule −1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1), Monocyte chemo-attractant protein-1 (MCP-1) and Endothelial-1 (ET-1), down regulates anti-atherogenic molecules and implicated in the first stage of the atherosclerosis process via endothelial cell activation.

On the other hand, high fat diet will cause body fat mass increment which can influence the level of resistin and cause insulin resistance and inflammation. Low High Density Lipoprotein (HDL), high triglyceride and high Low Density Lipoprotein (LDL) are characterize as atherogenic dyslipidemia while resistin will induce dyslipidemia to accelerate atherogenesis [70]. A study done by Leon et al. [74] reported that food rich in saturated fat and triglyceride were found to have positive relationship on the increment of resistin concentration. Atherogenesis is a process of forming plaques in the intima layer of arteries. It developed progressively with inflammation and lipid accumulation varying significantly among individuals [75]. Thus, resistin provide macrophages with overly large lipid fractions inducing dyslipidemia and result in the progress of atherosclerosis plaques.
